The mechanism of action of alpha-naphthoflavone as an inhibitor of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced CYP1A1 gene expression.
The mechanism of action of alpha-naphthoflavone as an inhibitor of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced CYP1A1 gene expression.
复制标题
α-萘黄酮作为 2,3,7,8-四氯二苯并-对二恶英诱导的 CYP1A1 基因表达抑制剂的作用机制。
DOI：
10.1016/0003-9861(90)90416-v
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发表时间：
1990
影响因子：
3.9
通讯作者：
Safe,S
中科院分区：
文献类型：
--
作者：
Merchant,M;Arellano,L;Safe,S
用α-萘啶酮（αNF）（10−8，10−7，10− 6 m）处理大鼠肝癌H-4-II E细胞，仅在10− 6 m处对乙氧基试卤灵O-脱乙基酶（EROD）活性和细胞色素P4501 A1 mRNA水平产生最低程度的诱导。相比之下，2，3，7，8-四氯二苯并二恶英（TCDD）在10− 8和10− 9 m处引起最大或接近最大的诱导反应。在TCDD（10− 9 m）和TCDD + αNF（共处理）的时程研究中，αNF在细胞最初暴露于化学品后6-24 h显著抑制TCDD诱导的EROD活性和细胞色素P4501 A1 mRNA水平。此外，在存在或不存在10−8、10−7和10− 9 m αNF的情况下，用10− 9 mTCDD处理细胞显示，后者化合物以浓度依赖性方式抑制TCDD的诱导作用，并且这些抑制作用可以部分地被更高浓度的TCDD（10− 8 m）克服。用[~ 3 H]TCDD处理大鼠肝癌H-4-II E细胞，在60 min内，细胞核[~ 3 H]TCDD受体复合物水平（38 fmol/mg蛋白质）开始迅速升高，4 h内下降到10 fmol/mg蛋白质以下，并在24 h内保持相对稳定。然而，在用[3 H]TCDD（10− 9 m）和αNF（10− 6 m）处理的细胞中，在整个24小时的时间过程中，细胞核[3 H]TCDD受体复合物的水平<5 fmol/mg蛋白质。结合αNF竞争性抑制[3 H]-TCDD与胞质芳烃（Ah）受体结合的结果，表明αNF通过直接竞争胞质Ah受体结合位点抑制TCDD介导的CYP 1A 1基因转录和翻译诱导。
Treatment of rat hepatoma H-4-II E cells with α-naphthoflavone (αNF) (10−8, 10−7, 10−6m) resulted in only minimum induction of ethoxyresorufinO-deethylase (EROD) activity and cytochrome P4501A1 mRNA levels only at 10−6m. In contrast, 2,3,7,8-tetrachlorodi-benzo-p-dioxin (TCDD) caused maximum or near maximum induction responses at 10−8and 10−9m. In a timecourse study with TCDD (10−9m), and TCDD plus αNF (cotreated), αNF significantly inhibited the induction of EROD activity and cytochrome P4501A1 mRNA levels by TCDD for 6–24 h after initial exposure of the cells to the chemicals. In addition, treatment of the cells with 10−9mTCDD in the presence or absence of 10−8, 10−7, and 10−9mαNF showed that the latter compound inhibited the induction effects by TCDD in a concentration-dependent manner and these inhibitory effects could be overcome, in part, by a higher concentration of TCDD (10−8m). Treatment of the rat hepatoma H-4-II E cells with [3H]TCDD showed that within 60 min, there was an initial rapid increase in nuclear [3H]TCDD receptor complex levels (38 fmol/mg protein) which decreased to less than 10 fmol/mg protein within 4 h and remained relatively constant for up to 24 h. However, in cells treated with [3H]TCDD (10−9m) plus αNF (10−6m) the levels of the nuclear [3H]TCDD receptor complex were <5 fmol/mg protein throughout the 24-h time course. These data, coupled with the results which indicate that the αNF competitively inhibits the binding of [3H]-TCDD to the cytosolic aryl hydrocarbon (Ah) receptor, suggest that αNF inhibits the TCDD-mediated induction of CYP1A1 gene transcription and translation by direct competition for cytosolic Ah receptor binding sites.